(a) Field of the Invention
The invention relates to the use of a leukotriene B4 (LTB4) agent as an adjuvant to vaccine preparations.
(b) Description of Prior Art
Vaccines have been used for decades for the prevention of diseases in humans. The efficacy of any vaccine preparation largely depends on its immunogenicity, i.e., their ability to induce strong humoral and cellular immunity. However, many vaccines currently in use have moderate efficacy due to their weak immunogenicity. Because of this, several attempts have been made to supplement vaccine preparations with adjuvants in order to increase the ability of a given vaccine to induce a strong immunity. Unfortunately, most of the substance used as adjuvants have undesirable side effects, which prevent their use in humans.
Adjuvants have been used extensively to improve the generation of an immune response following immunization with a particular antigen, especially in laboratory animals. However, classical and effective adjuvants, such as the Freund's adjuvant, cause undesirable side effects, which prevent their use in humans. Less toxic adjuvants, such as aluminum hydroxide (alum), although relatively well tolerated, do not offer the same degree of immunopotentiation as the Freund's adjuvant.
Thus, because of a lack of effective adjuvant, vaccines for human use are often poorly immunogenic and multiple immunization regimens are required to achieve proper protection against a given pathogen. In addition, long-lasting immunity is often lost in absence of repeated immunization. Intense efforts are therefore devoted to the identification of new effective adjuvants to complement currently used vaccines.
Leukotriene B4 (LTB4) is a known natural molecule. LTB4 is a metabolite of arachidonic acid derived from the 5-lipoxygenase pathway. LTB4 has many reported biological properties. In particular, LTB4 is considered as a potent pro-inflammatory compound; its most important biological activity is its chemotactic and chemokinetic effects on leukocytes. Indeed, LTB4 has been shown to be a potent chemoattractant for human polymorphonuclear leukocytes, monocytes and macrophages, both in vitro and in vivo. LTB4 also activates other leukocyte functions such as degranulation and superoxide anion synthesis. Because of these pro-inflammatory effects, LTB4 is considered as a putative component in defense mechanisms. Moreover, LTB4 is synthesized by inflammatory cells such as polymorphonuclear leukocytes, monocytes and macrophages and is also synthetized by B lymphocytes.
The effects of LTB4 on B cell activity have been previously studied under in vitro experimental conditions. B lymphocyte proliferation, expression of activation markers such as CD23 and immunoglobulin secretion were evaluated. Most studies reached similar conclusions stating that LTB4 by itself, in absence of exogenous cytokines or stimuli (Protein A or S. aureus), had no effects on B cell proliferation or immunoflobulin synthesis (IgG or IBM) (Yamaoka, K. A., et al., 1989, J. Immunol. 143: 1996-2000; Dugas, B., et al., 1990, J. Immunol. 145:3406-3411; Odlander, B., et al., 1989, Int. J. Tiss. Reac. XI(6):277-289). The only observable effects of LTB4 on B lymphocytes were recorded when combined to a stimulating agents (Protein A or S. aureus) and cytokines. A conflicting paper also reports that LTB4 had an inhibitory effects on the synthesis of immunoglobulin from B lymphocytes (Rola-Plecszczynski, M., et al., 1982, Biochem. Biophys. Res. Commun. 108:1531-1537). It thus appear that LTB4 by itself does not stimulate B cell functions and perhaps may even negatively influence it under defined experimental conditions.
It would be highly desirable to be provided with an adjuvant with greater efficacy than the currently used hydroxide aluminum based adjuvant and which would not present the undesirable side effects of the more potent Freund's adjuvant.